THE PHARMACOKINETICS OF VENLAFAXINE WHEN GIVEN IN A TWICE-DAILY REGIMEN

The comparative bioavailability of the novel antidepressant venlafaxin e and its pharmacologically active metabolite O-desmethylvenlafaxine w as assessed when venlafaxine was given orally twice daily (75 mg bid) or 3 times daily (50 mg tid). Eighteen healthy subjects participated i n an open-label, randomized, two-period, crossover study lasting 12 da ys. Each subject was randomly assigned to take venlafaxine according t o a bid or a tid regimen through day 8 and was crossed over to the oth er regimen on days 9 to 12. The daily dose was titrated up to 150 mg/d and was held constant on days 5 to 12. Plasma samples for quantitatio n of venlafaxine and O-desmethylvenlafaxine were obtained during a 24- hour steady-state interval on days 8 and 12. Analysis of variance show ed no significant differences between the two venlafaxine regimens for peak concentration (C-max), area under the curve during 24 hours (AUC (0-24)), trough concentration, or fluctuation ratio for venlafaxine or O-desmethylvenlafaxine in plasma, The bioequivalence ratios for C-max and AUC(0-24) of both compounds were calculated to compare the bid re gimen and the tid regimen. The mean value for each of the 4 ratios was between 96 and 100%, and the 90% confidence limits around each ratio were within 90 to 110%. These results indicate that dividing a daily 1 50-mg venlafaxine dose into 2 or 3 doses provides equivalent total exp osure and peak plasma concentrations of venlafaxine and O-desmethylven lafaxine, its active metabolite. Therefore, based on pharmacokinetic c onsiderations, it appears that the same daily dose of venlafaxine can be given in either two or three divided doses without compromising eff icacy.